Shikonin alleviates the biotoxicity produced by pneumococcal pneumolysin.

AIMS: Streptococcus pneumoniae (S. pneumoniae) is a common pathogen that can cause severe infections in humans. Pneumolysin (PLY) is an important virulence trait of S. pneumoniae and has cytotoxicity, genotoxicity and pro-inflammatory activity; it is essential for the pathogenesis of S. pneumoniae pneumonia and is an anti-virulence target of small molecule drug development. The treatment options for this microbe were limit due to the ubiquitous antibiotic resistance; therefore, new drugs and treatment strategies are needed. METHODS: Shikonin was selected by drug screening based on haemolysis assays, and its mechanism of suppressing PLY toxicity was determined by oligomerization assay. Meanwhile, the in vitro cell viability assays and in vivo experiments were performed to explore the capability of shikonin to protect cells and tissue from S. pneumoniae-mediated damage. KEY FINDINGS: Shikonin was found to significantly decrease PLY-induced haemolytic activity, cytotoxicity and genotoxicity via lessening the formation of oligomers; moreover, the agent can reduce the mortality of mice caused by lethal pneumonia and mitigate the injury of target organs as well. SIGNIFICANCE: We suggest that shikonin could be a potent candidate for a novel therapeutic or auxiliary substance in the treatment of infections encountering insufficient vaccines and antimicrobial resistance to traditional antibiotics.

Isorhamnetin Attenuates Staphylococcus aureus-Induced Lung Cell Injury by Inhibiting Alpha-Hemolysin Expression.

Staphylococcus aureus, like other gram-positive pathogens, has evolved a large repertoire of virulence factors as a powerful weapon to subvert the host immune system, among which alpha-hemolysin (Hla), a secreted pore-forming cytotoxin, plays a preeminent role. We observed a concentration-dependent reduction in Hla production by S. aureus in the presence of sub-inhibitory concentrations of isorhamnetin, a flavonoid from the fruits of Hippophae rhamnoides L., which has little antibacterial activity. We further evaluate the effect of isorhamnetin on the transcription of the Hla-encoding gene hla and RNAIII, an effector molecule in the agr system. Isorhamnetin significantly down-regulated RNAIII expression and subsequently inhibited hla transcription. In a co-culture of S. aureus and lung cells, topical isorhamnetin treatment protected against S. aureus-induced cell injury. Isorhamnetin may represent a leading compound for the development of anti-virulence drugs against S. aureus infections.

Null genotypes of glutathione S-transferase µ1 and glutathione S-transferase θ1 are associated with osteosarcoma risk: A meta-analysis.

Glutathione S-transferase (GST) genetic polymorphisms has been reported to be associated with osteosarcoma; however, the results of previous studies are conflicting. Thus, in the present study, a meta-analysis was conducted to investigate the effects of GSTM1 and GSTT1 polymorphisms on osteosarcoma risk. A literature search was performed in the PubMed, Cochrane Library and China National Knowledge Infrastructure databases to identify case-control studies published prior to March 2014. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. In addition, Begg's test was used to measure publication bias. Sensitivity analysis were performed to ensure the accuracy of the results. The meta-analysis results demonstrated no significant association between the null genotype of GSTM1 and osteosarcoma risk (OR=0.83; 95% CI, 0.37-1.85). By contrast, the results revealed a significant association for the comparison of null vs. non-null genotypes of GSTT1 (OR=1.54; 95% CI, 1.09-2.19). In conclusion, the GSTT1 null genotype may be associated with an increased risk of developing osteosarcoma. Further studies with larger sample sizes and well-designed methodologies are required to verify these conclusions.